Pyridine carboxylic acids are important intermediate as pharmaceuticals, agrochemicals and food additives. In particular, 3-pyridine carboxylic acid, also called nicotinic acid or niacin is commercially most significant and is used as a precursor of vitamin B3. The 4-pyridine carboxylic acid, also called isonicotinic acid, is used as raw materials for anti-tubercular drugs. It is also regarded as the corrosion inhibitor, electroplate additive, photosensitive resin stabilizer and nonferrous metals floating agent. The 2-pyridine carboxylic acid is used as anti-acne agent and intermediate for several drugs.
Several processes are reported in the prior art for the production of pyridine carboxylic acids. The known processes differ from each other with respect to the different chemical processes followed.
The processes for the preparation of 3-pyridine carboxylic acid also called nicotinic acid are mainly from liquid phase reaction, vapor phase reaction, electrochemical oxidation and also biological oxidation.
U.S. Pat. No. 2,586,555 reported liquid phase direct oxidation using nitric acid and sulphuric acid at temperatures from 75 to 300° C. and with yields up to 77%. U.S. Pat. No. 2,905,688 reported the process using nitric acid under pressure conditions.
GB757958 discloses preparation of nicotinic and isonicotinic acids by oxidation of alkylpyridines with nitric acid in the vapor phase using B2O3 and SeO2 as catalysts.
Japanese patent No. 07,233,150 discloses the method for producing nicotinic acid by the process involving liquid-phase oxidation of β-picoline. Thus, β-picoline, Co(OAc)2.4H2O, Mn(OAc)4.4H2O and 47% aq. HBr are added to an autoclave, pressurized to 100 atm with air and allowed to react at 210° C. for 3 h. The autoclave is cooled, depressurized and cooled to 5° C. and the precipitated crystals are filtered, washed with toluene, and dried to give nicotinic acid, wherein a total of 32% β-picoline is converted and 19% nicotinic acid is converted into β-picoline. To the filtrate β-picoline, Co(OAc)2.4H2O, Mn(OAc)4.4H2O and 47% aq. HBr are added and resulting mixture is added to the autoclave and pressurized to 100 atm with air, allowed to react at 210° C. for 3 h, and processed to give nicotinic acid with 34% β-picoline conversion ratio and 20.8% conversion of β-picoline into nicotinic acid.
U.S. Pat. No. 7,560,566 reported a process for the production of nicotinic acid which involves contacting 3-methylpyridine with hydrogen peroxide, in the presence of catalyst manganese bromide, in the presence of water as solvent under supercritical conditions close to the supercritical point. The results show good selectivity for nicotinic acid of around 95% at a conversion of about 30%. 3-Pyridine carboxaldehyde is detected with a yield of 1-2%.
Chinese Patent No. CN1090618 discloses bromide-free pyridine carboxylic acids preparation by liquid phase oxidation. 3-Methylpyridine is autoclaved with cobalt acetate, manganese acetate, hydrogen bromide, and aq. acetic acid at 210° C. with supplying air, and then the reaction mixture was hydrogenated over Pd/C at 130° C. and 6 kg/cm2 hydrogen for 2 h to give nicotinic acid containing 17 ppm bromine.
Disadvantages of these processes are the high salt production, as well as the production of large streams of waste water. The yield and selectivity's of these processes are quite low and lots of by-products are formed. In some of the processes involving bromides, further purification for removing bromine is required which makes the process complicated and increasing the process steps thereby increasing manufacturing cost. Also, because of high temperature and pressure conditions and multi step processing the processes reported in the prior art are capital intensive.
U.S. Pat. No. 5,002,641 reported the electrochemical synthesis of niacin and other N-heterocyclic compounds. An electrolyte medium is prepared containing 85 parts water by weight, 10 parts α-picoline, and 5 parts picolinic acid. The solution is charged into an undivided cell and electrolyzed using an anodized tin anode with a platinum cathode at a constant current between 0.1 and 1.0 A (10-100 mAcm−2). Analysis of the electrolyte indicated an increase in picolinic acid corresponding to 83% current efficiency. The process is also used for the oxidation of quinoline and other methyl pyridine compounds.
European Patent No. 442430 discloses a microbiological process for oxidizing β-picoline to nicotinic acid with a yield of 50% after a reaction time of 16 hours. The unsatisfactory space-time yield and the costly separation of the biomass from the nicotinic acid make industrial application of this process disadvantageous.
The vapor phase oxidation can be done either by ammoxidation of 3-picoline to 3-cyanopyridine followed by liquid phase hydrolysis of 3-cyanopyridine to niacin or directly by the oxidation of 2-methyl-5-ethylpyridine.
Mikhalovskaya et at in Izvestiya Natsional'noi Akademii Nauk Respubliki Kazakhstan, Seriya Khimicheskaya, 2003, 2, 75 have reported oxidation of 4-methylpyridine to isonicotinic acid on Va-Ti—Zr oxide catalyst. 4-Pyridine aldehyde was formed as intermediate oxidation product which on hydrolysis gave isonicotinic acid product.
The vapor phase oxidation of 4-picoline using different catalysts in fluidized bed has been reported. Yang et at in Gaoxiao Huaxue Gongcheng Xuebao, 2007, 448 have reported preparation of isonicotinic acid by vapor-phase oxidation of 4-picoline over V—Ti—Cr—Al—P oxide catalyst prepared by an impregnation method. Under optimum conditions, the product yield reached 82%.
Afanas'eva et al in Khimiya Geterotsiklicheskikh Soedinenii, 1968, 1, 142 have reported the preparation of isonicotinic acid by vapour phase catalytic oxidation of trimethylol-4-picoline. The process involves reacting 1 mole of trimethylol-4-picoline, 150-200 moles H2O2 and 125-200 moles oxygen for 0.35-0.45 sec. contact time on a tin vanadate catalyst in a 280 mm quartz-tube, 20 mm in diameter to give isonicotinic acid in 65% yield.
In the recent past, there are literature references which reported vapor phase oxidation of β-picoline using vanadia based catalyst.
U.S. Pat. No. 3,803,156 provides a process for producing pyridine carboxylic acid, which comprises contacting methylpyridine, molecular oxygen-containing gas, and water with solid oxidation catalyst containing a vanadium compound bonded with oxygen in the vapor phase to produce pyridine carboxylic acid. In this process, minor amount of oxides of germanium, tin, indium, niobium, tantalum, gallium, and zirconium are used as promoter. This process has disadvantages of high reaction temperature and a large amount of water which in turn increases the energy consumption during purification.
U.S. Pat. No. 5,728,837 discloses the process for preparing nicotinic acid with a yield of 82-86%. The disclosed process involves gas phase oxidation of β-picoline with oxygen in the presence of water vapor over vanadia based catalyst at a temperature of 250-290° C. and mole ratio of oxygen:β-picoline 15-40:1 and water:β-picoline 10-70:1. Further, the nicotinic acid is isolated by crystallization in a tube crystallizer at a temperature of 160-200° C.
European Patent No. 762933 also discloses a process for the preparation of a highly selective catalyst for the ammoxidation of alkylpyridines to cyanopyridines which on further hydrolysis give pyridine carboxylic acid. The catalyst composition disclosed is VaTibZrcOx, wherein a is 1, b is 7.5-8, c is 0.5, x represents the number of oxygen atoms.
U.S. Pat. No. 2,494,204 discloses the process for the preparation of picolinic acid. The process involves reacting equimolar amounts of cyanogen and butadiene in the vapor phase at 480° C., contact time of 87 seconds to give 18.1% of 2-cyanopyridine which is converted to picolinic acid.
U.S. Pat. No. 6,229,018 reported the preparation of nicotinic acid by the direct oxidation of β-picoline in the gas phase, wherein water and β-picoline are fed separately into the catalyst. The catalyst, vanadium oxide is supported on titanium oxide which is produced by sulfuric acid method and the support titanium oxide has high specific surface area. It has been disclosed that when the specific surface area of the titanium dioxide support is greater than 250 m2/g, and the amount of vanadium oxide content is at least 20% by weight, the yields are high. However, if the titanium oxide having low specific surface area and vanadium oxide in low amount is used for the oxidation process, the yield of the nicotinic acid is reduced. Carbon dioxide produced in the process is partially recycled back in the reactor to bring about an additional improvement in the nicotinic acid yield. The recovery of niacin, involves desublimation process at 235° C. by installing a tubular crystallizer at the reactor outlet. German Patent No. 19822788 discloses the oxidation of 5-ethyl-2-methylpyridine with vanadium oxide based catalyst, supported on Al2O3 and/or ZrO2 with specific surface 1-50 m2/g. The process involves passing 5-ethyl-2-methylpyridine (2 mg/min), air (80 mL/min), and H2O (0.2 g/min) over 10 g of LiV6O15/ZrSiO4 catalyst at 320° C. for 900 min to give 100% conversion and a 66% yield of nicotinic acid.
The direct catalytic vapor phase oxidation of alkyl pyridines has lot of advantages over other processes. The vapor phase process uses air as oxidant instead of stoichiometric large excess of chemical oxidizing agents. The reaction is carried out at atmospheric pressure. The only solvent used is water. The process is highly selective therefore waste generation is very less. Another advantage is that there are very few unit operations necessary to obtain the pure product.
However, most of the processes reported in the prior art are carried out at very small scale in laboratory. As oxidation of alkyl pyridine with oxygen is a highly exothermic reaction, under the given process conditions at larger scale, there is generation of hot spots, on the top of the catalyst bed at feed introduction point because of higher concentration of alkyl pyridine at initial stage. This results in runaway conditions of the reaction temperature, and therefore not very safe to operate at large scale. Also the non uniform temperature profile across the catalyst bed affects selectivity as well as quality of the product.
Also, the recovery from the reaction mass has been reported by following desublimation process, incorporating crystallizer. Design of a suitable crystallizer for large volume is very challenging and is not commercially proven.
There are also many other literature references which proposes alternate methods with or without use of organic solvents for recovery and purification of pyridine carboxylic acids from the reaction mass but none of the prior art processes can be practiced at large scale because of many disadvantages associated with the process to be feasible for large scale production. Hence, these processes can only be operated at laboratory scale and are not suitable at larger scale.
Moreover, the processes disclosed in the prior art include multiple steps for extraction and isolation to obtain the desired products. The prior art processes involves time-consuming purification process at each step, which results in wasteful material, consequently making the process costly and uneconomical. Further, the processes can be used for producing small batches of the desired products in low yield and at higher costs, hence making the processes unsuitable for large-scale production.
In view of the increasing demand for producing pyridine carboxylic acid of high purity and yield, it is therefore desirable to develop a commercially and economically viable process for large scale industrial manufacturing of pyridine carboxylic acid with high purity and yield which can address the above mentioned problems associated with the known processes. Further, the process should be temperature controlled and involve use of fewer purification steps.